Blood glucose levels are used as a biomarker for metabolic syndrome, and people are diagnosed as having diabetes if their fasting blood glucose levels exceed 126 mg/dL. Moreover, even if fasting blood glucose levels fall within a normal range, some people have 2-hour postprandial blood glucose levels as high as 140 to 200 mg/dL and are diagnosed as having impaired glucose tolerance (or postprandial hyperglycemia). Recent epidemiological studies have reported that impaired glucose tolerance increases the risk of cardiovascular disorders (see NPL 1 and NPL 2). Further, it has been reported that exercise therapy and/or medication not only suppresses the development of type II diabetes from impaired glucose tolerance, but also significantly suppresses the onset of hypertension (see NPL 3).
In view of the foregoing, suppression of postprandial hyperglycemia is of importance in suppressing the onset of diabetes and/or metabolic syndrome, and there has accordingly been an increasing demand for drugs used to control postprandial hyperglycemia.
As agents for improving postprandial hyperglycemia, α-glucosidase inhibitors have been conventionally used widely, which inhibit sugar hydrolases and thereby delay sugar absorption from the small intestine. In addition to these agents, there have been developed other agents with a new mechanism of action for improving postprandial hyperglycemia.
On the mammalian small intestinal epithelium, sodium-dependent glucose transporter 1 (SGLT1) is expressed at a high frequency. It is known that SGLT1 serves depending upon sodium and plays a role in active transport of glucose or galactose in the small intestine. Based on these findings, pyrazole derivatives have been reported, which inhibit SGLT1 activity to thereby suppress glucose absorption from a meal and can be used for prevention or treatment of postprandial hyperglycemia (see PTL 1 to PTL 6). On the other hand, sodium-dependent glucose transporter 2 (SGLT2) is expressed at a high frequency in the kidney, and glucose once filtered by the glomeruli is reabsorbed via SGLT2 (see NPL 4). Moreover, it has been reported that upon inhibition of SGLT2 activity, sugar excretion into urine is facilitated to induce a hypoglycemic action (see NPL 5). SGLT2 inhibitors are characterized in that they have an excellent hypoglycemic action to lower casual blood glucose levels, but their action to control postprandial hyperglycemia is low, unlike SGLT1 inhibitors. Further, there is a report of C-phenyl glucitol derivatives which inhibit not only SGLT1 activity but also SGLT2 activity at the same time (see PTL 7).
On the other hand, in the case of drugs required to be administered continuously, including agents for improving postprandial hyperglycemia, it is important to have a wide margin of safety between the therapeutic dose and the toxic or side effect dose. Particularly in the case of drugs prone to remain in the body, it is difficult to control their dosage required for treatment, so that an excessive drug effect will be developed as a result of summing residual drugs remaining in the body, thus leading to unexpected toxicity and side effects. For example, it is known that cationic drugs whose molecule has a hydrophilic group (e.g., a tertiary amine) and a hydrophobic group (e.g., an aromatic ring) bind to phospholipids through hydrophobic bonding and are taken up by lysosomes and hence accumulated in all organs in the body. As typical examples, chloroquine is shown to cause retinopathy, while perhexiline gives rise to a problem of neuropathy because it induces changes in the lung and cerebellum (see NPL 6).
Thus, drugs are desired to be rapidly excreted from the body after developing their efficacy. In particular, agents for improving postprandial hyperglycemia that must be administered continuously are desired to be free from the problem of accumulation in the body.